Conformationally semi-constrained quinoxaline 2,3-diones as neuroprotective agents

ABSTRACT

Described are neuroprotective agents of Formula I                    
     wherein 
     R is an amino acid or nitrogen heterocyclic ring which is saturated or unsaturated of from 5 to 8 members which may have additional oxygen or sulfur atoms therein. The other provisions or substituents are described in the specification.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of U.S. Ser. No. 09/025295 filed Feb. 13,1998 which is now abandoned, having benefit of 60/046,626 filed May 16,1997.

BACKGROUND OF THE INVENTION

The present invention concerns conformationally semi-constrained analogsof substituted quinoxaline 2,3-diones having utility as glutamatereceptor antagonists. The quinoxaline 2,3-dione system is substituted byan amino acid derivative or nitrogen heterocyclic ring which includesbioisosteres of carboxylic acid derivatives via a carbon atom linkage.The compounds are active as excitatory amino acid receptor antagonistsacting at glutamate receptors, including either or bothN-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors such as theI-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptorand the kainate receptor. The invention also relates, therefore, to theuse of those quinoxaline-2,3-diones as neuroprotective agents fortreating conditions such as cerebral ischemia or cerebral infarctionresulting from a range of phenomena, such as thromboembolic orhemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest,status epilepticus, perinatal asphyxia, anoxia such as from drowning,pulmonary surgery, and cerebral trauma, as well as to treat chronicneurodegenerative disorders such as Alzheimer's Disease, Parkinsonism,and Huntington's Disease, and seizure disorders and pain. The compoundsof the present invention may also be useful in the treatment ofschizophrenia, epilepsy, anxiety, pain, and drug addiction.

Excessive excitation by neurotransmitters can cause the degeneration anddeath of neurons. It is believed that this degeneration is in partmediated by the excitotoxic actions of the excitatory amino acids (EAA)glutamate and aspartate at the N-methyl-D-aspartate (NMDA) receptor, theI-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor,and the kainate receptor. AMPA/kainate receptors may be referred tojointly as non-NMDA receptors. This excitotoxic action is consideredresponsible for the loss of neurons in cerebrovascular disorders such ascerebral ischemia or cerebral infarction resulting from a range ofconditions, such as thromboembolic or hemorrhagic stroke, cerebralvasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatalasphyxia, anoxia such as from drowning, pulmonary surgery, and cerebraltrauma, as well as lathyrism, Alzheimer's Disease, Parkinson's Disease,and Huntington's Disease.

Several classes of quinoxalinedione derivatives have been disclosed asglutamate (EAA) receptor antagonists. For example, among excitatoryamino acid receptor antagonists recognized for usefulness in thetreatment of disorders are those that block AMPA receptors (Bigge C. F.and Malone T. C., Curr. Opin. Ther. Pat., 1993:951; Rogawski M. A.,TiPS, 1993;14:325). AMPA receptor antagonists have prevented neuronalinjury in several models of global cerebral ischemia (Li H. and BuchanA. M., J. Cerebr. Blood Flow Metab., 1993;13:933; Nellg{dot over (a)}rdB. and Wieloch T., J. Cerebr. Blood Flow Metab., 1992;12:2) and focalcerebral ischemia (Bullock R., Graham D. I., Swanson S., and McCullochJ., J. Cerebr. Blood Flow Metab., 1994;14:466; Xue D., Huang Z.-G.,Barnes K., Lesiuk H. J., Smith K. E., and Buchan A. M., J. Cerebr. BloodFlow Metab.,1994;14:251). AMPA antagonists have also shown efficacy inmodels for analgesia (Xu X.-J., Hao J.-X, Seiger A., andWiesenfeld-Hallin Z., J. Pharmacol. Exp. Ther., 1993;267:140), andepilepsy (Namba T., Morimoto K., Sato K., Yamada N., and Kuroda S.,Brain Res., 1994;638:36; Brown S. E. and McCulloch J., Brain Res.,1994;641:10; Yamaguchi S. I., Donevan S. D., and Rogawski M. A.,Epilepsy Res., 1993;15:179; Smith S. E., Durmuller N., and Meldrum B.S., Eur. J. Pharmacol., 1991;201:179). AMPA receptor antagonists havealso demonstrated promise in chronic neurodegenerative disorders such asParkinsonism (Klockgether T., Turski L., Honoré T., Zhang Z., Gash D.M., Kurlan R., and Greenamyre J. T., Ann. Neurol., 1993;34(4):585-593).

Excitatory amino acid receptor antagonists that block NMDA receptors arealso recognized for usefulness in the treatment of disorders. NMDAreceptors are intimately involved in the phenomenon of excitotoxicity,which may be a critical determinant of outcome of several neurologicaldisorders. Disorders known to be responsive to blockade of the NMDAreceptor include acute cerebral ischemia (stroke or cerebral trauma, forexample), muscular spasm, convulsive disorders, neuropathic pain, andanxiety, and may be a significant causal factor in chronicneurodegenerative disorders such as Parkinson's Disease (Klockgether T.and Turski L., Ann. Neurol., 1993;34:585-593), human immunodeficiencyvirus (HIV) related neuronal injury, amyotrophic lateral sclerosis(ALS), Alzheimer's Disease (Francis P. T., Sims N. R., Procter A. W.,and Bowen D. M., J. Neurochem., 1993;60(5):1589-1604), and Huntington'sDisease. (See Lipton S., TINS, 1993;16(12):527-532; Lipton S. A. andRosenberg P. A., New Eng. J. Med., 1994;330(9):613-622; and Bigge C. F.,Biochem. Pharmacol., 1993;45:1547-1561 and references cited therein.)NMDA receptor antagonists may also be used to prevent tolerance toopiate analgesia or to help control withdrawal symptoms from addictivedrugs (European Patent Application 488,959A).

The compounds of the instant invention differ from the art in that theyprovide non-coplanar compounds with greater solubility and, therefore,better ability to penetrate the blood-brain barrier. These are importantattributes in pharmaceuticals. It is a further object to coverconformationally semi-constrained quinoxaline-2,3-dione derivatives.

SUMMARY OF THE INVENTION

Described are quinoxaline-dione compounds of Formula I

wherein

R is an amino acid, a derivative thereof, or nitrogen heterocyclic ringwhich is saturated or unsaturated of from 5 to 8 members which may haveadditional oxygen or sulfur atoms therein and which may be substitutedby one or more substituents selected from:

alkyl of from 1 to 4 carbon atoms,

hydroxyl,

alkoxy of from 1 to 4 carbon atoms,

—CF₃,

—CN,

-amino,

—C(O)R₁₁, or

—(CH₂)_(n)-aryl of from 6 to 12 carbon atoms;

R must be attached through a carbon to the quinoxalinyl ring;

R₁ is H, alkyl of from 1 to 4 carbon atoms, phosphonoalkyl of from 1 to4 carbon atoms, phosphoroalkyl of from 1 to 4 carbon atoms, carboxyalkylof from 1 to 4 carbon atoms, —(CH₂)_(m)C(O)R₁₁, or hydroxy;

R₂ is hydrogen, hydroxy, or amine;

R₃ and R₄ are each independently H, alkyl of from 1 to 4 carbon atoms,cycloalkyl of from 5 to 7 carbon atoms, alkenyl of from 2 to 6 carbonatoms, halogen, haloalkyl of from 1-6 carbon atoms, nitro, cyano,SO₂CF₃, CH₂SO₂R₇, (CH₂)_(m)CO₂R₇, (CH₂)_(m)CONR₇R₈, (CH₂)_(m)SO₂NR₈R₉,or NHCOR₇;

R₅ is H, alkyl of from 1 to 4 carbon atoms, alkenyl of from 2 to 6carbon atoms, cycloalkyl of from 5 to 7 carbon atoms, halogen, haloalkylof from 1 to 4 carbon atoms, —(CH₂)_(m)aryl of from 6 to 10 carbonatoms, nitro, cyano, SO₂CF₃, (CH₂)_(m)CO₂R₉, (CH₂)_(m)CONR₉R₁₀,SO₂NR₉R₁₀, SO₂R₇, (CH₂)_(m)SO₂R₇, NHCOR₉, —(CH₂)_(m)heterocyclic of from6 to 10 atoms which may contain nitrogen, oxygen, sulfur, and/or—(CH₂)_(n)R;

R₅ may be joined at R₄ to form a cyclic aromatic or a heterocyclic ringof from 5 to 7 members which may contain nitrogen, oxygen, or sulfur;

R₇, R₈, R₉, and R₁₀ are each independently selected from hydrogen, alkylof from 1 to 4 carbon atoms, cycloalkyl of from 5 to 7 carbon atoms,haloalkyl of from 1 to 4 carbon atoms, or —(CH₂)_(m)R₁₁;

R₁₁ is alkyl or alkoxy of from 1 to 4 carbon atoms, hydroxy, or amino;

m is an integer of from 0 to 4;

n is an integer of from 0 to 4;

or a pharmaceutically acceptable salt thereof.

Preferred compounds are those of Formula I wherein

R is an amino acid attached via an alkyl side-chain to thequinoxaline-2,3-dione ring at C-5 or C-6. The amino acid is R or S orRS(±). The point of attachment is I- to the carboxylic acid moiety,e.g.,

wherein

p is an integer of from 0 to 4;

R₁₂ is —OH, alkoxy, or —NR₇R₈;

R₁₃ is H, OH, C(O)CH₃, protecting groups such as alkyl, aralkyl, oraryl, Boc, CBZ, FMOC;

wherein

m′ is an integer of from 1 to 3;

X, Y, Z, and W are each independently S, O, N, or C.

Or R is a nitrogen heterocyclic ring of 5 to 7 members with additionaloxygen or sulfur atoms therein, and which includes bioisosteres ofcarboxylic acid, ester or amide, attached to the 5- or 6-quinoxalinylside-chain via a carbon in the ring.

Some of the preferred compounds of the invention are selected from:

[(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-amino] aceticacid tert-butyl ester;

[(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-methylamino]-aceticacid, tert-butyl ester;

3-[(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-amino]-propionicacid, tert-butyl ester,

(S)-2-[(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-amino]-3-phenylpropionicacid, tert-butyl ester;

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic aciddimethylamide;

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acidmethylamide;

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acidbenzylamide;

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid,4-methoxy-benzylamide;

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acidphenylamide;

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid(4-methoxyphenyl)amide;

(2,3-Dimethoxy-6-methyl-7-nitro-quinoxalin-5-yl)-piperazin-1-ylmethanone;

[1,4]Diazepan-1-yl-(2,3-dimethoxy-6-methyl-7-nitro-quinoxalin-5-yl)methanone;and

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid,p-tolylamide.

For a description of bioisosteres see Annual Reports in Med. Chem.,1986;21:283; Chem. Soc. Reviews, 1979:563; Chemical Reviews,1996;96:3147. Common bioisosteres are:

Common preferred heterocycles are:

wherein R′ and R″ are independently H, alkyl, cycloalkyl,heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, haloalkyl,CO₂R₇, CONR₇R₈, (CH₂)_(m)SO₂NR₈R₉, C(O)R₇, SO₂CF₃, and CH₂SO₂R₇.

Also described is a method for or treatment of neurodegenerativedisorders including ALS, cerebral ischemia caused by cerebral trauma,stroke, hypoglycemia, heart attack, and surgery; anxiety andschizophrenia; and chronic neurodegenerative disorders such asHuntington's Disease, ALS, Parkinsonism, and Alzheimer's Disease. Thecompounds of this invention may also be employed as analgesics or in thetreatment of epilepsy.

DETAILED DESCRIPTION

The present invention is concerned with compounds of Formula I. Thecompounds are prepared according to one or more of the followingschemes.

TABLE ANALOGS OF 14

No. R Yield 14a

77% 14b

74% 14c

68% 14d

57% 14e Me₂N 100%  14f MeNH 76% 14g

84% 14h

47% 14i

62% 14j

66% 14k

86% 14l

87% 14m

65%

GENERAL EXPERIMENTAL Scheme I

Step (a) involves formation of isatoic anhydride as shown in formula 2by reacting the anthranilic acid derivative as shown in formula 1 withphosgene in the presence of an inorganic base such as aqueous sodiumcarbonate. The reaction is carried out at temperatures ranging from 0°C. to room temperature.

Step (b) involves bromination of the isatoic anhydride as shown informula 2 to the bromo derivative as shown in formula 3 by reacting theanhydride with bromine in solution of AcOH/TFA at temperatures rangingfrom 0° C. to room temperature. Aqueous workup yields the desired bromoderivative.

Step (c) involves nitration of the isatoic anhydride shown in formula 3with nitrating mixtures, preferably KNO₃/H₂SO₄, to give the nitroderivative as shown in formula 4. The reaction is carried out attemperatures ranging from 0° C. to room temperature, preferably doingthe addition of the nitrating mixtures at 0° C..

Step (d) involves opening of the isatoic anhydride derivative as shownin formula 4 with an alcohol, preferably methanol. The reaction iscarried out at reflux temperatures to give the desired methyl ester asshown in formula 5.

Step (e) involves catalytic reduction of the nitroaniline derivative asshown in formula 5 to the corresponding o-phenylenediamine derivative asshown in formula 6 using Raney Nickel as the catalyst with proticsolvents, preferably methanol, under hydrogen atmosphere of up to 50 psi(in the presence of a base, preferably triethylamine).

Step (f) involves cyclization of the o-phenylenediamine derivative asshown in formula 6 to the corresponding quinoxaline-2,3-dione derivativeas shown in formula 7. The diamine derivative is reacted with oxalicacid derivatives, preferably dimethyl oxalate, in a polar solvent suchas methanol or ethereal solvent such as THF or aqueous acids such ashydrochloric acid. The reaction is carried out at reflux temperatures.

Step (g) involves nitration of the quinoxaline-2,3-dione derivative asshown in formula 7 to the corresponding 7-nitro derivative as shown informula 8. The nitration is carried out with a nitrating mixture ofKNO₃/H₂SO₄, and product is isolated by normal aqueous workup.

Step (h) involves hydrolysis of the ester derivative as shown in formula8 to the corresponding acid derivative as shown in formula 9. Thehydrolysis is carried out in the presence of a base, preferably KOH, ina water soluble solvent such as dioxane or methanol.

Scheme II

Step (a) involves the formation of protected hydrazide derivative asshown in formula 3 of the acid derivative as shown in formula 1 bycoupling a monoprotected hydrazine derivative, preferably Boc-hydrazine,in the presence of coupling agents such as CDI or EDAC or via a reactiveintermediate such as mixed anhydride, preferably via EDAC, in thepresence of activating agents such as HOBt and DMAP in polar solventssuch as dimethylformamide. The product is isolated by a normal aqueousworkup.

Step (b) involves the deprotection of the hydrazine derivative shown informula 3 to the corresponding hydrazide derivative shown in formula 4.The deprotection is carried out under acidic conditions such as aqueousHCl, or HCl saturated in organic solvent such as chloroform or dioxane.Alternatively, hydrazide derivative 4 is synthesized as shown in Step(c). Thus, compound shown in formula 4 is synthesized by reactingcarboxylic acid ester derivative as shown in formula 2 with hydrazinewith or without a solvent such as dioxane, THF or DMF, preferably neat,at temperatures ranging from room temperature to reflux, preferablyreflux. The product is isolated by aqueous workup.

Step (d) involves cyclization of the hydrazide derivative as shown informula 4 to the corresponding oxadiazole derivative as shown in formula6 by reacting the hydrazide derivative with cyanogen bromide in thepresence of inorganic bases such as sodium carbonate, sodium bicarbonateor potassium bicarbonate, preferably potassium bicarbonate, in polarsolvents such as water, DMF or DMSO, preferably water, at temperaturesranging from room temperature to reflux, preferably elevatedtemperatures of 70° C. to 80° C.

Step (e) involves cyclization of the hydrazide derivative as shown informula 4 to the corresponding oxadiazole derivative as shown in formula5 by reacting the hydrazide derivative with bifunctional acylating agentsuch as phosgene or diethyl carbonate, preferably phosgene, in ahydrocarbon solvent such as benzene or toluene, or ethereal solvent suchas THF, preferably THF, at temperatures ranging from room temperature toreflux, preferably room temperature.

Step (f) involves cyclization of the hydrazide derivative as shown informula 4 to the corresponding oxadiazole derivative as shown in formula7 by reacting the hydrazide derivative as shown in formula 4 with adisulfide agent such as carbon disulfide in the presence of inorganicbases such as sodium carbonate, sodium hydroxide or potassium carbonateor potassium hydroxide. Reaction is worked up under acidic conditions togive the desired product.

Steps (g) and (h) involve the cyclization of semicarbazide derivativeformed in situ by reacting the ester derivative as shown in formula 2with semicarbazide salt in the presence of an alkoxide base such assodium methoxide or potassium t-butoxide, preferably sodium methoxide,in polar solvent such as methanol or butanol, preferably methanol, attemperatures ranging from room temperature to reflux. Acidic workup(Step h), preferably with methanolic HCl, would give the desiredtriazole derivative as shown in formula 6.

Scheme III

Step (a) involves the cyclization of hydrazide derivative as shown informula 1 to the corresponding triazole derivative as shown in formula 2with an isocyanate derivative such as methyl isocyanate in the presenceof a polar solvent such as ethanol in the presence of a base such assodium or potassium hydroxide. Acidic workup, preferably with aqueousHCl, gave the desired product.

Step (b) involves the conversion of oxadiazole derivative as shown informula 3 to the corresponding triazole derivative as shown in formula 4by reacting the oxadiazole derivative as shown in formula 3 withhydrazine in the presence of polar solvent such as ethanol attemperatures ranging from room temperature to reflux, preferably reflux,to give the product after acid workup, preferably with HCl.

Scheme IV

Step (a) involves the formation of the thiosemicarbazide derivative asshown in formula 2 by reacting the acid derivative as shown in formula 1in the presence of coupling agents such as CDI or EDAC, or via activatedacid derivatives such as anhydride or acid chloride; preferably EDAC inthe presence of activating agent such as HOBt in polar solvents such asDMF at temperatures ranging from room temperature to 60° C., preferablyroom temperature.

Step (b) involves the cyclization of thiosemicarbazide derivative asshown in formula 2 to the corresponding triazole derivative as shown informula 3 in the presence of inorganic bases such as potassium hydroxideor alkoxide bases such as sodium methoxide in polar solvents such asmethanol. Alternatively, Step (c) shows that the semicarbazidederivative can be cyclized to form the corresponding thiadiazolederivative as shown in formula 4 under acidic conditions. Thecyclization is carried out in the presence of acids such asmethanesulfonic acid in polar solvents such as DMF at elevatedtemperatures, preferably around 100° C.

Scheme V

Step (a) involves the coupling of the acid derivative as shown informula 1 with the hydrazine derivative as shown in formula 2 in thepresence of coupling agents such as CDI or EDAC, preferably EDAC, in thepresence of activating agents such as HOBt in polar solvents such as DMFat temperatures ranging from room temperature to 40° C., preferably roomtemperature.

Step (b) involves cyclization of the hydrazide derivative as shown informula 3 to the corresponding thiadiazole derivative as shown informula 4 under acidic conditions, preferably p-toluenesulfonic acid, orunder oxidative conditions using perchloric acid in acetic anhydride.The thiomethyl derivative as shown in formula 4 is deprotected as shownin Step (c), preferably using sodium thiomethoxide in polar solventssuch as DMF at temperatures ranging from room temperature to 100° C. togive the corresponding thiol derivative as shown in formula 5.

Scheme VI

Step (a) involves the coupling of the acid derivative as shown informula 1 with the acetyl hydrazine derivative in the presence ofcoupling agents such as CDI or EDAC, preferably CDI, in the presence ofactivating agents such as HOBt in polar solvents such as DMF to givehydrazide derivative as shown in formula 2.

Step (b) involves cyclization of the hydrazide derivative as shown informula 2 to the corresponding oxadiazole derivative as shown in formula3 via silylation of hydrazide derivative, preferably withhexamethyldisilazane, followed by cyclization involving desilylation inthe presence of a base such as TBAF in a high boiling solvent such aschlorobenzene at temperatures ranging from room temperature to reflux,preferably at reflux.

Step (c) involves alkylation of the alkali metal salt such as sodium orpotassium salt of the acid derivative as shown in formula 1 withalpha-bromo ketone derivative as shown in formula 4 in the presence of abase such as tetrabutylammonium bromide in a high boiling solvent suchas toluene or chlorobenzene, preferably toluene. The ester is isolatedby normal aqueous workup.

Step (d) involves cyclization of the ester as shown in formula 5 to thecorresponding oxazole derivative as shown in formula 6 in the presenceof a base like ammonium acetate in an acidic solvent such as aceticacid.

Scheme VII

Step (a) involves chlorination of the 5-carboxylic acid derivative ofquinoxaline-2,3-dione as shown in formula 1 to the corresponding chloroderivative shown in formula 2, using chlorinating agents such asphosphoryl chloride or phosphous pentachloride or thionyl chloride,preferably a mixture of phosphoryl chloride and phosphoruspentachloride. The reaction is carried out at temperatures rangingbetween 80° C. to reflux, preferably reflux. Volatile material isevaporated and the reaction mixture quenched over ice followed byaqueous inorganic base workup using aqueous solution of sodiumbicarbonate or sodium carbonate, preferably sodium bicarbonate. Theproduct is isolated on adjusting the pH to 6 using acids such as aceticacid or HCl, preferably acetic acid.

Step (b) involves methoxylation of the 2,3-dichloroquinoxalinederivative as shown in formula 2 to the corresponding 2,3-dimethoxycompound as shown in formula 3. The reaction is carried out using analkali metal alkoxide, preferably sodium methoxide, in hydroxylatedsolvent such as methanol at temperatures ranging from room temperatureto reflux, preferably reflux, and product isolated by aqueous workup.

Step (c) involves chlorination of the 5-carboxylic acid derivative asshown in formula 3 to the corresponding acid chloride derivative asshown in formula 4 using chlorinating agents such as oxalyl chloride,thionyl chloride or phosphorus trichloride, preferably thionyl chlorideat temperatures ranging from room temperature to reflux, preferablyreflux.

Step (d) involves generation of the a-haloketone as shown in formula 5from the 5-carboxylic acid chloride derivative as shown in formula 4 viaa diazoketone generated by reacting the acid chloride with diazomethane.The diazoketone intermediate on treatment with acids like HBr or HCl,preferably HBr, gave the corresponding a-bromomethyl ketone as shown informula 5.

Step (e) involves cyclization of the α-haloketone as shown in formula 5to the corresponding imidazolyl derivative as shown in formula 7 byreacting the compound shown in formula 5 with an amidine derivative,preferably with benzhydrylamidine derivative as shown in formula 6 in achlorinated solvent such as dichloromethane or chloroform, preferablychloroform (Heterocycles, 1996;42:517).

Step (f) involves deprotection of the imino ether moieties in formula 7to the corresponding amide derivative as shown in formula 8. Thereaction is carried out using trimethylsilyl iodide or trimethylsilylchloride/KI mixture or inorganic acids such as aqueous HCl or HBr,preferably 5N HCl at temperatures ranging from room temperature to 100°C., preferably 80° C.

Scheme VIII

Step (a) involves generation of the amide as shown in formula 2 from theacid chloride derivative as shown in formula 1 by reacting the acidchloride with ammonia in a sealed tube. The reaction is also carried outin an ethereal solvent such as dioxane or THF, preferably dioxane, andbubbling in gaseous ammonia.

Step (b) involves dehydration of the amide as shown in formula 2 to givethe corresponding cyano derivative as shown in formula 3. The reactionis carried out using dehydrating agents such as polyphosphoric acid withor without a solvent.

Step (c) involves generation of the amidine derivative as shown informula 4 by treating the cyano derivative as shown in formula 3 withhydroxylamine hydrochloride in the presence of an inorganic base such aspotassium carbonate or sodium carbonate in an alcoholic solvent such asmethanol or ethanol, preferably ethanol.

Step (d) involves cyclization of the amidine derivative as shown informula 4 to the corresponding oxadiazole derivative as shown in formula5 by reacting the amidine derivative with an acid chloride, preferablywith acetyl chloride, in the presence of an organic base such aspyridine or triethylamine, preferably pyridine, using base as thesolvent at temperatures ranging from room temperature to reflux,preferably reflux.

Step (e) involves the cleavage of the imino ether functionality as shownin formula 5 to the corresponding amide derivative as shown in formula6. The cleavage is carried out in the presence of reagents such astrimethylsilyl iodide or trimethylsilyl chloride/KI, or inorganic acidssuch as HCl or HBr, preferably aqueous HCl.

Scheme IX

Step (a) involves cyclization of the hydroxyamidine derivative as shownin formula 1 to the corresponding substituted oxadiazole derivative asshown in formula 2 by reacting the hydroxyamidine derivative with anacid chloride, preferably with trichloroacetylchloride, in the presenceof an organic acid such as acetic acid or trichloroacetic acid,preferably trichloroacetic acid, at temperatures ranging from roomtemperature to reflux, preferably above 100° C., J. Med. Chem.,1994;37:2421.

Step (b) involves cyclization of the hydroxyamidine derivative as shownin formula 1 to the corresponding oxadiazoline derivative as shown informula 3 by reacting the hydroxyamidine derivative with a reactivebifunctional acylating agent such as ethyl chloroformate or phosgene,preferably ethyl chloroformate, in the presence of inorganic bases suchas potassium carbonate in polar solvents such as acetone at temperaturesranging from room temperature to reflux, preferably reflux.Alternatively, the cyclization can be carried out by reactinghydroxyamidine derivative with diethyl carbonate in the presence ofalkali metal bases such as sodium or potassium ethoxide in an alcoholicsolvent such as ethanol at temperatures ranging from room temperature toreflux, preferably reflux.

Step (c) involves cleavage of the imino ethers in compounds shown informula 2 or 3 to give the corresponding amide derivatives as shown informula 4. The deprotection can be carried out in the presence of silylagents such as trimethylsilyl iodide or trimethylsilyl chloride/KImixture or in the presence of inorganic acids such as aqueous HCl orHBr.

Scheme X

Step (a) involves the cyclization of the amide derivative as shown informula 1 to the corresponding oxadiazole derivative as shown in formula2 by reacting the amide initially with a diketo compound such asdimethylacetamide dimethyl acetal to give the corresponding acylamidinederivative in situ. The acylamidine derivative on treatment withhydroxylamine hydrochloride in the presence of inorganic bases such assodium bicarbonate or sodium hydroxide or sodium acetate, preferablysodium hydroxide, in an aqueous solution, gave the cyclized product asshown in formula 2.

Step (b) involves the cleavage of the imino ethers in compound shown informula 2 to the corresponding amide derivative as shown in formula 3using conditions described in Scheme IX, Step (c).

Scheme XI

Step (a) involves the generation of the aminoamidinyl intermediate asshown in formula 2 from the 5-cyano-2,3-dimethoxy-quinoxaline derivativeas shown in formula 1 by treating the cyano derivative with hydrazine inthe presence of a base like sodium hydride using ethereal solvent suchas THF or dioxane, preferably THF. The reaction can be carried out attemperatures ranging from room temperature to reflux, preferably reflux.

Step (b) involves cyclization of the aminoamidine derivative as shown informula 2 to the corresponding thiadiazole derivative as shown informula 3 by treating compound 2 with carbon disulfide at temperaturesranging from room temperature to reflux, preferably reflux.

Step (c) involves deprotection of the imino ethers in compound shown informula 3 using conditions described in Scheme IX, Step (c).

Scheme XII

Step (a) involves the formation of the tetrazole derivative as shown informula 2 by reacting the corresponding cyano derivatives as shown informula 1 with tri-n-butyltin azide in an ethereal solvent such asdioxane or THF, preferably dioxane, at temperatures ranging from roomtemperature to reflux preferably around 60° C.

Step (b) involves deprotection of the imino ethers in compound shown informula 2 using conditions discussed in Scheme IX, Step (c) to give theamide derivative shown in formula 3.

Scheme XIII

Step (a) involves the chlorination of the quinoxaline-2,3-dionederivative as shown in formula 1 to the corresponding 2,3-dichloroderivative as shown in formula 2 using conditions discussed in SchemeVII, Step (a).

Step (b) involves methoxylation of the dichloro derivative shown informula 2 to the corresponding 2,3-dimethoxy compound as shown informula 3 using alkali metal alkoxide, preferably sodium methoxide, inalcoholic solvent such as methanol at temperatures ranging from roomtemperature to reflux, preferably reflux.

Step (c) involves reduction of the ester moiety in the compound shown informula 3 to the corresponding hydroxymethyl derivative shown in formula4 using a borohydride reagent, preferably lithium borohydride, in analcoholic solvent, preferably ethanol, at temperatures ranging from roomtemperature to 50° C., preferably room temperature.

Step (d) involves bromination of the hydroxymethyl derivative shown informula 4 using brominating agents such as HBr or phosphorus tribromideor thionyl bromide, preferably HBr, in solvents such as acetic acid.

Step (e) involves converting the bromomethyl derivative to thecorresponding cyanomethyl derivative as shown in formula 5 using alkalimetal cyanide, preferably potassium cyanide, in polar solvents such asDMSO or DMF, preferably DMSO.

Step (f) involves a cycloaddition reaction involving the cyanomethylderivative shown in formula 5 with a dipolarophile such astri-n-butyltin azide to give the tetrazole derivative as shown informula 6. The reaction can be carried out as described in Scheme XII,Step (a).

Step (g) involves deprotection of the imino ethers as shown in formula 6to the corresponding amide derivative as shown in formula 7 as describedin Scheme IX, Step (c).

Scheme XIV

Step (a) involves alkylation of the bromomethyl derivative shown informula 1 with diethylacetamidomalonate sodium salt, generated bytreating diethylacetamidomalonate with sodium hydride in an etherealsolvent such as THF or polar solvent such as DMF to give the amino acidprecursor, which on treatment with a base such as aqueous sodiumhydroxide in alcoholic solvent such as ethanol gave the desiredN-acetyl-amino acid derivative as shown in formula 2.

Step (b) involves cyclization of the amino acid intermediate as shown informula 2 to the corresponding oxazolidinone derivative as shown informula 3 by treating the amino acid intermediate with formaldehyde inacidic solvent such as acetic acid in the presence of catalyticp-toluenesulfonic acid. On aqueous workup, the desired oxazolidinone isobtained (Walter M. W., et al., Tetrahedron Letters, 1995;36:7761).

Step (c) involves the optional resolution step of the stereoisomers ofthe amino acid derivative shown in formula 2. The resolution is carriedout by using hog kidney acylase in aqueous solution at pH 7.5. TheD-isomer is isolated and crystallized. The optically pure amino acidderivative, as shown in formula 2a, can also be used to synthesize theoxazolidinone derivative shown in formula 3 as a single enantiomer.

Step (d) involves deprotection of the imino ethers as shown in formulas2a and 4 to the corresponding amide derivatives as shown in formulas 4and 4a. The deprotection can be carried out as described in Scheme IX,Step (c).

Scheme XV

Step (a) involves the reaction of the organomagnesium salt of2-bromo-3-nitrotoluene as shown in formula 1, prepared by the reactionof compound 1 and fresh magnesium turnings in ether, with an aminoketone such as 1-methyl-3-piperidone derivative in an ethereal solventsuch as diethyl ether or THF or dioxane. The reaction mixture isquenched with aqueous ammonium chloride solution (Step b), and the crudeproduct is heated to about 100° C. with a protic solvent such as aceticacid or HCl. The tetrahydropyridinyl derivative as shown in formula 2 isisolated as a free base on quenching the reaction with saturated sodiumbicarbonate or ammonia solution.

Step (c) involves the reduction of the tetrahydropyridinyl derivative asshown in formula 2 to give the corresponding piperidinyl derivative asshown in formula 3. The reduction is carried out under catalytichydrogenation conditions using Pd/C (5% to 20%), preferably 20%, andhydrogen gas at 50 psi in a hydroxylated solvent such as methanol.

Step (d) involves acetylation of the amino group in compound shown informula 3 followed by nitration and deprotection to give thenitroaniline derivative as shown in formula 4. The acetylation iscarried out by heating the solution of compound 3 in acetic anhydride toreflux or by treating a solution of compound 3 in a solvent such asdichloromethane or THF, preferably dichloromethane with acetyl chloridein the presence of a base such as triethylamine or pyridine and acatalytic amount of DMAP. In the case of pyridine as the base, the amineis dissolved in pyridine. The nitration is carried out using nitratingmixtures such as potassium nitrate and sulfuric acid or nitric acid inacetic anhydride, preferably nitric acid in acetic anhydride. Removal ofthe acetyl group is done by treatment with an inorganic base such assodium hydroxide in hydroxylated solvent such as methanol or water.

Step (e) involves reduction of the o-nitroaniline derivative as shown informula 4 to the corresponding o-phenylenediamine intermediate as shownin formula 5. The reduction is carried out under catalytic hydrogenationconditions using Raney Nickel or Pd/C as the catalysts and hydrogen gasunder pressures of up to 50 psi in alcoholic solvents such as methanol.The reduction is also carried out under metal/acid conditions such asFe/HCl or Sn/HCl, preferably Fe/HCl.

Step (f) involves formation of quinoxaline-2,3-dione derivative as shownin formula 6 by reacting the o-phenylenediamine derivative shown informula 5 with an alpha-dicarbonyl derivative such as oxalyl chloride ordimethyl oxalate or oxalic acid, preferably dimethyl oxalate, in anethereal solvent such as THF or protic solvent such as methanol oraqueous HCl, preferably THF.

Step (g) involves nitration of the quinoxaline-2,3-dione derivativeshown in formula 6 to give the corresponding nitro derivative as shownin formula 7 using reagents such as KNO₃/H₂SO₄ or HNO₃ or nitroniumtetrafluoroborate, preferably KNO₃/H₂SO₄.

Scheme XVI

Step (a) involves protection of the amino group of the anilinederivative as shown in formula 1. The preferred protecting group is Bocand is incorporated by treating the aniline derivative with Bocanhydride in the presence of an aqueous base such as sodium hydroxide orsodium carbonate, preferably sodium carbonate.

Step (b) involves the coupling of 2-chloropyridine with the N-Bocaniline derivative in the presence of a base such as n-BuLi in anethereal solvent such as anhydrous THF. The coupling is carried out attemperatures ranging from 0° C. to room temperature to give the productas shown in formula 2.

Step (c) involves reduction of the pyridyl ring in the compound shown informula 2 to give the corresponding reduced compound as shown in formula3. Initially, the pyridinyl moiety is quaternized with an alkylatingagent such as methyl iodide or methyl triflate, preferably methyliodide, in the presence of solvent such as THF or methanol. Thequaternary salt is then reduced to the tetrahydro stage usingborohydride reducing agents such as sodium borohydride or sodiumcyanoborohydride, preferably sodium borohydride, in solvents such asethanol. The tetrahydropyridyl ring is fully reduced to the piperidinylring via catalytic hydrogenation using Pd/C as the catalyst and hydrogengas (up to 50 psi) in solvents such as THF or ethanol.

Step (d) involves nitration of the piperidinyl compound shown in formula3 to give the corresponding nitroaniline derivative as shown in formula4. The nitration is carried out using conditions described in Step (d)of Scheme XV.

Step (e) involves reduction of the nitroaniline derivative shown informula 4 to the corresponding o-phenylenediamine derivative as shown informula 5. The reduction is carried out as described in Step (e) inScheme XV.

Step (f) involves formation of the quinoxaline-2,3-dione derivative asshown in formula 6 by reacting oxalic acid derivative with theo-phenylenediamine as shown in formula 5. The reaction conditions aredescribed in Step (f), Scheme XV.

Step (g) involves nitration of the quinoxaline-2,3-dione derivative asshown in formula 6 to give the corresponding nitro derivative as shownin formula 7. The reaction conditions are described in Step (g) inScheme XV.

Scheme XVII

Step (a) involves Pd catalyzed coupling of bromobenzene derivative shownin formula 1 with 2-lithio-N-Boc-pyrrolidino or N-Boc-piperidinocompound as shown in formula 2 generated in situ by reacting N-Bocpyrrolidine or piperidine with sec-BuLi in a solvent such as THF to givethe corresponding cyclic amine derivative as shown in formula 2. Thereaction is carried out as reported in the literature by Dieter, et al.,Tetrahedron Letters, 1995;36:3613-3616. The reaction is carried out inthe presence of catalytic amounts of CuCN and Pd[(p-OCH₃-Ph)₃P]₄ orPdCl₂(PPh₃)₂.

Step (b) involves nitration of the aniline derivative shown in formula 2to give the corresponding o-nitroaniline derivative as shown in formula3. The conditions for nitration are described in Step (d), Scheme XV.

Step (c) and (d) involve the reduction of the o-nitroaniline derivativeto the corresponding o-phenylenediamine derivative as shown in formula 3and cyclization of the o-phenylenediamine derivative as shown in formula4 to the corresponding quinoxaline-2-3-dione derivative as shown informula 5, respectively. The conditions for both these steps have beendescribed in Steps (e) and (f) of Scheme XV, respectively.

Step (e) involves nitration of the quinoxaline-2,3-dione derivative asshown in formula 5 to the corresponding nitro derivative as shown informula 6. The conditions for the nitration are described in Step (g) ofScheme XV.

Scheme XVIII

Step (a) involves coupling of the bromobenzene derivative as shown informula 1 with amino acid chloride as shown in formula 2 via generationof the organomagnesium salt using fresh magnesium turnings in a solventsuch as ether. The ketone derivative as shown in formula 3 is isolatedon quenching the reaction with aqueous ammonium chloride followed bynormal aqueous workup (Macor J. E., et al., J. Organic Chem.,1994;59:7496).

Step (b) involves the reduction of the nitro group of the nitrobenzenederivative as shown in formula 3 under catalytic hydrogenationconditions to give the corresponding aniline derivative as shown informula 4. The preferred catalyst is Raney Nickel, and the solvent ispreferably methanol and hydrogen gas at around 50 psi.

Steps (c) and (d) involve acetylation of the aniline derivative as shownin formula 4 followed by nitration to give the o-nitroaniline derivativeas shown in formula 5. The conditions for acetylation and nitration aredescribed in Step (d) of Scheme XV.

Step (e) involves deprotection of the amino group and reduction of theketo nitroaniline derivative as shown in formula 5 to the correspondingo-phenylenediamine derivative as shown in formula 6. The acetyl group issaponified using an aqueous base such as sodium or potassium hydroxide,preferably sodium hydroxide. The reduction is carried out using LAH as areducing agent in an ethereal solvent such as anhydrous THF.Alternatively, the keto group can be reduced under Wolff-Kishnerconditions, i.e., via the hydrazone formation followed by the catalytic(Ra-Ni) reduction of the nitro group.

Steps (f) and (g) involve the formation of the quinoxaline-2,3-dionederivative followed by nitration of the quinoxaline-2,3-dione derivativeas shown in formula 7 from the o-phenylenediamine derivative as shown informula 6. The conditions for the quinoxaline-2,3-dione formation andnitration are described in Steps (f) and (g) of Scheme XV.

Scheme XIX

Step (a) involves formation of the benzyl bromide derivative as shown informula 2 from the benzyl alcohol derivative as shown in formula 1 fromthe benzylalcohol derivative as shown in formula 1. The bromination iscarried out using brominating agents such as phosphorus tribromide,thionyl bromide or CBr₄/PPh₃, preferably CBr₄/PPh₃, in an etherealsolvent such as ether or THF, preferably ether.

Step (b) involves alkylation of the N-Boc imidazolone derivative asshown in formula 3 with the benzyl bromide derivative as shown informula 2. The reaction involves generation of an anion using a lithiumbase such as LDA in ethereal solvent such as THF followed by addition ofthe benzyl bromide solution (Harding M. M., et al., TetrahedronAsymmetry, 1994;5:1793-1804).

Steps (c) and (d) involve reduction of the o-nitroaniline derivative asshown in formula 4, followed by the cyclization of theo-phenylenediamine derivative to the corresponding quinoxaline-2,3-dionederivative as shown in formula 5. The conditions for reduction andcyclization are described in Steps (e) and (f) of Scheme XV,respectively.

Step (e) involves the nitration of the quinoxaline-2,3-dione derivativeand simultaneous hydrolytic ring opening of the imidazolone side-chainas shown in formula 5 to the corresponding 7-nitro-quinoxaline-2,3-dionederivative as shown in formula 6. The conditions for nitration aredescribed in Step (g) of Scheme XV.

Scheme XX

Step (a) involves alkylation of the anion of 2,3-diethoxy pyrazine(Schollkopf chiral auxiliary) derivative as shown in formula 2 withbenzyl bromide derivative as shown in formula 1. The anion is generatedusing a lithium base, preferably n-BuLi, and the reaction can be carriedout as described earlier by Cook, et al., Synthetic Communications,1995;25:3883-3900 to give the product as shown in formula 3.

Steps (b) and (c) involve reduction of the o-nitroaniline derivative asshown in formula 2 to the o-phenylenediamine derivative and formation ofthe corresponding quinoxaline-2,3-dione derivative as shown in formula4, respectively. The conditions for reduction and cyclization aredescribed in Steps (e) and (f) in Scheme XV, respectively.

Step (d) involves the nitration of the quinoxaline-2,3-dione derivativeas shown in formula 3 to the corresponding 7-nitro derivative as shownin formula 4. During nitration the 2,5-diethoxypyrazine side-chain ishydrolyzed to give the amino acid side-chain as shown in formula 5. Theconditions for nitration are as described in Step (g) of Scheme XV.

The aforementioned abbreviations have the following meanings:

Boc tertiary Butyloxycarbonyl CDI 1,1′-Carbonyldimidazole CBZBenzyloxycarbonyl DEAD Diethyl azodicarboxylate DEE Diethyl ether DMAP4-Dimethylaminopyridine DMF Dimethylformamide DMSO Dimethyl sulfoxideEDAC Ethyl-3-(3-dimethylamino)-propylcarbodiimide FMOC9-Fluorenylmethyloxycarbonyl HOBt 1-Hydroxybenzotriazole LAH LithiumAluminum Hydride NMP n-Methyl pyrrolidone TEA Triethylamine TFATrifluoroacetic acid THF Tetrahydrofuran

Some preferred compounds are shown below. The compounds are preferablyNO₂ derivatives for R₄.

wherein Y is oxygen or sulfur.

Some of the compounds of Formula I are capable of further forming bothpharmaceutically acceptable acid addition and/or base salts. These formsare within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono- and bicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate,oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate,mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate,lactate, maleate, tartrate, methanesulfonate, and the like. Alsocontemplated are salts of amino acids such as arginate and the like andgluconate, galacturonate (see, for example, Berge S. M., et al.,“Pharmaceutical Salts,” J. Pharma. Sci., 1977;66:1).

The acid addition salts of said basic compounds can be prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the presentinvention.

Pharmaceutically acceptable base addition salts can be formed withmetals or amines, such as alkali and alkaline earth metals or organicamines. Examples of such metals used as cations are sodium, potassium,magnesium, calcium, and the like. Examples of suitable amines areN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (seeBerge, Supra, 1977).

The base addition salts of said acidic compounds can be prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner. The free acid formmay be regenerated by contacting the salt form with an acid andisolating the free acid in the conventional manner. The free acid formsdiffer from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid for purposes of the presentinvention.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms andare intended to be encompassed within the scope of the presentinvention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms as well as the appropriate mixtures thereof.

In the compounds of Formula I the amino acid derivative is an ester, anamide, a hydrazide, or a semicarbazide. The term “alkyl” means astraight or branched hydrocarbon radical having from 1 to 6 carbon atomsand includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.

The term “carboxyalkyl” means alkyl as above and attached to a carboxygroup.

The term “phosphoroalkyl” means alkyl as above and attached to aphosphoro group.

The term “phosphonoalkyl” means alkyl as above and attached to aphosphono group.

The term “alkenyl” means a straight or branched unsaturated hydrocarbonradical having from 3 to 6 carbon atoms and includes, for example,2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl,3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and the like.

“Alkoxy” or “thioalkoxy” is O-alkyl or S-alkyl of from 1 to 6 carbonatoms as defined above for “alkyl”.

The term “aryl” means an aromatic radical which is a phenyl group, aphenyl group substituted by 1 to 4 substituents selected from alkyl asdefined above, alkoxy as defined above, thioalkoxy as defined above,hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined abovefor alkyl, dialkylamino as defined for alkyl, or 1,3-benzodioxol-5-yl.

The term “aralkyl” means aryl and alkyl as defined above and includesbut is not limited to benzyl, 2-phenylethyl, and 3-phenylpropyl; apreferred group is phenyl.

The term “heteroaryl” means a heteroaromatic radical which is 2-, 3-, or4-pyridinyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-thienyl, isoquinolines,quinolines, imidazolines, pyrroles, indoles, and thiazoles.

“Halogen” is fluorine, chlorine, bromine, or iodine.

The term “haloalkyl” means halogen and alkyl as defined above, forexample, but not limited to, trifluoromethyl and trichloromethyl.

“Alkylaryl” means aryl as defined above and alkyl as defined above, forexample, but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl; apreferred group is benzyl.

The term “heterocycloalkyl” means a nonaromatic ring with from 4 to 7members, with up to 4 heteroatoms for example, N, O, and S.

Common amino acid moiety means the naturally occurring I-amino acids,unnatural amino acids, substituted υ, K, Λ amino acids and theirenantiomers.

Common amino acids are: Alanine, υ-alanine, arginine, asparagine,aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine,isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,threonine, tryptophan, tyrosine, and valine.

Modified and unusual amino acids are as would occur to a skilled chemistand are, for example, but not limited to:

10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)glycine orI-Amino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid(Para-phenyl)phenylalanine;

3,3-Diphenylalanine;

3-Hydroxyproline;

4-Hydroxyproline;

N-Methylphenylalanine;

N-Methylaspartic acid;

N-Methylisoleucine;

N-Methylvaline;

Norvaline;

Norleucine;

Ornithine;

2-Aminobutyric acid;

2-Amino-4-pentanoic acid (Allylglycine);

N^(G)-Nitroarginine;

2-Amino-3-(2-amino-5-thiazole)propanoic acid;

2-Amino-3-cyclopropanepropanoic acid (Cyclopropylalanine);

Cyclohexylalanine (Hexahydrophenylalanine);

N-Methylcyclohexylalanine (N-Methylhexahydro-phenylalanine);

2-Amino-4,4(RS)-epoxy-4-pentanoic acid;

N^(im)-2,4-Dinitrophenylhistidine;

2-Aminoadipic acid;

2-Amino-5-phenylpentanoic acid (Homophenylalanine);

Methionine sulfoxide;

Methionine sulfone;

3-(1′-Naphthyl)alanine;

3-(2′-Naphthyl)alanine;

2-Amino-3-cyanopropanoic acid (Cyanoalanine);

Phenylglycine;

2-Aminopentanoic acid (Propylglycine);

2-Amino-6-(1-pyrrolo)-hexanoic acid;

2-Amino-3-(3-pyridyl)-propanoic acid (3-Pyridylalanine);

1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid;

2-Amino-3-(4-thiazolyl)-propanoic acid;

O-Tertiarybutyl-tyrosine;

O-Methyl-tyrosine;

O-Ethyl-tyrosine;

N^(in)-Formyl-tryptophan;

5H-Dibenzo[a,d]cycloheptenyl glycine;

9H-Thioxanthenyl glycine; and

9H-Xanthenyl glycine.

The compounds of the present invention can be prepared and administeredin a wide variety of routes of administration such as parenteral, oral,topical, rectal, inhalation and the like. Formulations will varyaccording to the route of administration selected. Examples are oral andparenteral dosage forms. Thus, the compounds of the present inventioncan be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally, orintraperitoneally. Also, the compounds of the present invention can beadministered by inhalation, for example, intranasally. Additionally, thecompounds of the present invention can be administered transdermally.The following dosage forms may comprise as the active component, acompound of Formula I or a corresponding pharmaceutically acceptablesalt of a compound of Formula I.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier can be a finely divided solid which is in amixture with the finely divided active component.

In tablets, the active component can be mixed with the carrier havingthe necessary binding properties in suitable proportions and compactedin the shape and size desired.

The powders and tablets preferably contain from 5% or 10% to about 70%of the active compound. Suitable carriers are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent can be dispersed homogeneously therein, as by stirring. Themolten homogenous mixture can be then poured into convenient sizedmolds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted for example from about 0.1 mg to 200 mg, preferablyabout 0.5 mg to 100 mg according to the particular application and thepotency of the active component. The composition can, if desired, alsocontain other compatible therapeutic agents.

In therapeutic use as agents for the treatment of neurologicaldisorders, the compounds utilized in the pharmaceutical methods of thisinvention can be administered at an initial dosage of about 0.01 mg toabout 200 mg/kg daily. A daily dose range of about 0.01 mg to about 50mg/kg is preferred. The dosages, however, may be varied depending uponthe requirements of the patient, the severity of the condition beingtreated, and the compound being employed. Determination of the properdosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

Having described the invention herein, listed below are preferredembodiment or working examples wherein all temperatures are degreesCentigrade and all parts are parts by weight unless otherwise indicated.

EXAMPLES Example 1

Scheme I procedure is followed as indicated below:

5-Methyl-isatoic anhydride (2)

To an aqueous solution of anthranilic acid (100 g, 0.66 mol) and sodiumcarbonate (0.7 mol) a solution of phosgene in toluene (362 mL, 1.93 M,0.7 mol) was added dropwise under vigorous stirring. The reactionbecomes a suspension and is stirred for additional 8 hours and filtered.The residue was treated with aqueous Na₂CO₃ and filtered. Washed withwater (4×150 mL) and dried.

Yield: 88.4 g, 75.4%. MS (CI) m/z 178 (M+1).

6-Bromo-5-methyl-isatoic anhydride (3)

To a suspension of 5-methyl-isatoic anhydride (9.2 g, 0.052 mol) in amixture of glacial acetic acid (60 mL) and TFA (30 mL), bromine (9.9 g,0.062 mol) was added under stirring at 5° C. Reaction mixture warmed toroom temperature and stirred˜5 hours. Poured in cold water and yellowppt filtered and washed with water and dried. Yield: 12.09 g, 90%.

MS (CI) m/z=257 (M+1).

6-Bromo-5-methyl-8-nitro-isatoic anhydride (4)

To a solution of 6-bromo-5-methyl-isatoic anhydride (12.03 g, 0.047 mol)in sulfuric acid (80 mL), potassium nitrate (5.05 g, 0.05 mol) was addedat room temperature under vigorous stirring. After stirringapproximately 8 hours, reaction mixture was poured over ice. The aqueoussuspension was stirred for 0.5 hour and filtered and washed with water(4×100 mL) and dried. Yield 10.8 g, 76%.

MS (CI) m/z=302 (M+1).

Methyl-2-amino-5-bromo-6-methyl-3-nitrobenzoate (5)

A mixture of 6-bromo-5-methyl-8-nitro-isatoic anhydride (17.48 g, 0.0580mol) in MeOH (180 mL) was heated at reflux for 3 hours. After standingat 0° C. for 2 to 3 hours, the precipitated product (5) was collectedand washed with MeOH. Yield 12.24 g, 73%.

2,3, -Diamino-6-methylbenzoate (6)

A mixture of methyl-2-amino-5-bromo-6-methyl-3-nitrobenzoate (5) (12.24g, 0.0423 mol) and 20% Pd on C (1.0 g) in 1:1 MeOH:THF (400 mL) withtriethylamine (5.9 mL, 0.042 mol) was hydrogenated for 2 hours under ahydrogen pressure of 50 psi. The catalyst was filtered off (celite), andthe filtrate was concentrated. The residue was taken up in EtOAc, andthe organic layer was washed with a minimal amount of water. The organiclayer was dried over sodium sulfate, filtered, and concentrated to give7.62 g (100%) product (6).

MS (APCI) m/z=181 (M+1).

Synthesis of6-Methyl-2,3-dioxo-1,2,3,4-tetrahydro-quinoxaline-5-carboxylic acid,methyl ester (7)

A solution of 2,3-diamino-6-methylbenzoic acid, methyl ester (compound6) (1.14 g, 6.35 mmol) and dimethyl oxalate (3.34 g, 28.5 mmol) in MeOH(30 mL) was refluxed for 6 days. Upon cooling to room temperature, theprecipitated product was collected and washed with a small amount ofMeOH to give 1.02 g (69%).

MS (APCI) m/z=235 (M+1).

Synthesis of6-Methyl-7-nitro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxaline-5-carboxylicacid methyl ester (8)

To a solution of6-methyl-2,3-dioxo-1,2,3,4-tetrahydro-quinoxaline-5-carboxylic acid,methyl ester (1.11 g, 4.74 mmol) in conc. H₂SO₄ (15 mL) at roomtemperature was added in one portion with vigorous stirring potassiumnitrate (0.529 g, 5.23 mmol). The reaction mixture was stirred for 23hours and poured over ice. The precipitated product was thoroughlywashed with water upon collection to give 1.28 g (97%).

MS (CI) m/z=280 (M+1).

Synthesis of6-Methyl-7-nitro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxaline-5-carboxylicacid (9)

To a suspension of6-methyl-7-nitro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxaline-5-carboxylicacid, methyl ester (0.80 g, 2.87 mmol) in THF (50 mL) was added aqueous1.0N NaOH (4.3 mL, 4.3 mmol), and the reaction mixture was refluxed for23 hours. The product is precipitated upon acidification with conc. HCLand recrystallized from water to give 0.73 g (96%).

MS (APCI) m/z=266 (M⁺+1).

2,3-Dichloro-6-methyl-7-nitro-quinoxaline-5-carboxylic acid methyl ester(10)

To a suspension of6-methyl-7-nitro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxaline-5-carboxylicacid methyl ester (8) (5.85 g, 0.021 mol) in anhydrousN,N-dimethylformamide (60 mL) under an atmosphere of nitrogen was addeddropwise a 20% phosgene solution in toluene 34.03 mL (0.068 mol). Duringthe course of addition a mild exotherm resulted, and all undissolvedmaterial went into solution. After addition was complete (approximately10 minutes), the reaction mixture was stirred at room temperature for 22hours and concentrated. The residue was triturated with methanol and anoff-white crystalline solid precipitated, 5.98 g (90%), mp 155-157° C.;¹H NMR (CDCl₃): δ 8.48 (s, 1H), 4.05 (s, 3H), 2.59 (s, 3H); MS (APCI):m/z 317 (M⁺+H)⁺, 315 (M−H)⁺.

Anal. Calcd. for C₁₁H₇Cl₂N₃O₄: C, 41.80; H, 2.23; N, 13.29; Cl, 22.43.Found: C, 41.74; H, 2.04; N, 13.23; Cl, 22.15.

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid methylester (11)

To a solution of sodium metal (washed with hexane) 119 mg (5.19 mmol)dissolved in anhydrous methanol (15 mL) under an atmosphere of nitrogenat room temperature was added portionwise2,3-dichloro-6-methyl-7-nitro-quinoxaline-5-carboxylic acid methyl ester(10, caution: exothermic) 655 mg (2.07 mmol). After the addition wascomplete (approximately 3 minutes), the reaction mixture was stirred for10 minutes and quenched with water. The off-white amorphous precipitatewas washed with water and methanol upon collection, 554 mg (87%), mp174-176° C.; ¹H NMR (CDCL₃): δ 8.39 (s, 1H), 4.16 (s, 3H), 4.14 (s, 3H),4.04 (s, 3H), 2.60 (s, 3H); MS (APCI): m/z 308 (M+H).

Anal. Calcd. for C₁₃H₁₃N₃O₆: C, 50.82; H, 4.26; N, 13.68. Found: C,50.65; H, 4.20; N, 13.39.

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid (12)

To a suspension of2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid methylester (11) (1.61 g, 5.24 mmol) in THF 20 mL was added a solution ofpotassium hydroxide (85%) in 20 mL water (0.86 g, 13.09 mmol). Afterstirring at room temperature for 20 hours, all solid went into solution.The reaction was allowed to continue for an additional 7 hours and wasthen cooled to 0° (ice water bath). Acidification with aqueous 1.0 Nhydrochloric acid produced a white, amorphous precipitate which wasrecrystallized from ethyl acetate to give 1.47 g (95%) product, mp258-260° C.; ¹H NMR (DMSO-d₆): δ 12.37 (br s, 1H), 8.09 (s, 1H), 3.93(s, 3H), 3.89 (s, 3H), 2.34 (s, 3H); MS (APCI): m/z 294 (M+H).

Anal. Calcd. for C₁₂H₁₁N₃O₆: C, 49.15; H, 3.78; N, 14.33. Found: C,49.19; H, 3.53; N, 14.28.

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13)

A mixture of 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylicacid (12) (500 mg, 1.70 mmol) in thionyl chloride (twice distilled overtriphenyl phosphite) (25 mL) was heated at reflux for 20 hours. Thereaction mixture was concentrated to an off-white solid which waspurified by elution through a flash column (4:1 hexanes:ethyl acetate),510 mg (96%), mp 162-164° C.; ¹H NMR (CDCl₃): δ 8.35 (s, 1H), 4.15 (s,3H), 4.03 (s, 3H), 2.55 (s, 3H); MS: m/z 312 (M+H).

Anal. Calcd. for C₁₂H₁₀ClN₃O₅: C, 46.24; H, 3.23; N, 13.48. Found: C,46.38, H, 3.32; N, 13.28.

[(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-amino] aceticacid tert-butyl ester (14a) (General procedure for synthesis ofcompounds 14b-m)

To a mixture of glycine tert-butyl ester hydrochloride 104 mg (0.67mmol) and triethylamine in 3 mL anhydrous tetrahydrofuran 0.26 mL (1.69mmol) under an atmosphere of nitrogen was added dropwise a solution of2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 200mg (0.64 mmol) in 7 mL anhydrous tetrahydrofuran at 0° C. After theaddition was complete (approximately 5 minutes), the reaction mixturewas stirred at room temperature for 24 hours, filtered, andconcentrated. The residue was taken up in ethyl acetate and the organicsolution was washed with water, saturated aqueous sodium chloride, driedover sodium sulfate, filtered and concentrated. The crude product waspurified by elution through a flash column (silica gel 60, 230-400 mesh,3:2 hexanes/ethyl acetate) to give a yellow oil which crystallized onstanding, 200 mg (77%), mp 125-126° C.; ¹H NMR (CDCl₃): δ 8.32 (s, 1H,8-H), 6.32 (br s, 1H, amide NH), 4.14 (d, 2H, J=5.1 Hz), 4.09 (s, 3H),3.99 (s, 3H), 2.54 (s, 3H), 1.47 (s, 9H, tert-butyl protons); MS (APCI):m/z 407 (M+H).

Anal. Calcd. for C₁₈H₂₂N₄O₇: C, 53.20; H, 5.46; N, 13.79. Found: C,53.24; H, 5.45; N, 13.55.

[(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-methylamino]-aceticacid, tert-butyl ester (14b)

Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonylchloride (13) 200 mg (0.64 mmol) and sarcosine tert-butyl esterhydrochloride 122 mg (0.67 mmol). Reaction was continued for 24 hours,and the crude product was eluted through a flash column (4:1hexanes:ethyl acetate), 200 mg (74%), mp 102-105° C.; ¹H NMR (CDCl₃): δ8.29 (s, 1H), 4.27 (br s, 2H), 4.02 (s, 3H), 3.96 (s, 3H), 3.35 (br s,3H), 2.54 (s, 3H), 1.41 (s, 9H); MS (APCI): m/z 421 (M+H).

Anal. Calcd. for C₁₉H₂₄N₄O₇: C, 54.28; H, 5.75; N, 13.33. Found: C,54.51; H, 5.76; N, 13.35.

3-[(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-amino]-propionicacid, tert-butyl ester (14c)

Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonylchloride (13) 250 mg (0.80 mmol) and β-alanine tert-butyl esterhydrochloride 153 mg (0.80 mmol). Reaction was continued for 2.5 hours,and the crude product was eluted through a flash column (3:2hexanes:ethyl acetate), 230 mg (68%), mp 140-142° C., R_(f) 0.47 (1:1hexanes:ethyl acetate); ¹H NMR (CDCl₃): δ 8.31 (s,1H), 6.37 (br s, 1H),4.08 (s, 3H), 3.97 (s, 3H), 3.74 (q, 2H, methylene protons, J=6.1 Hz),2.57 (t, 2H, J=6.3 Hz, J=6.1 Hz), 2.55 (s, 3H), 1.42 (s, 9H); MS (APCI):m/z 421 (M+H).

Anal. Calcd. for C₁₉H₂₄N₄O₇: C, 54.28; H, 5.75; N, 13.33. Found: C,54.25; H, 5.69; N, 13.00.

(S)-2-[(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-amino]-3-phenylpropionicacid, tert-butyl ester (14d)

Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonylchloride (13) 200 mg (0.64 mmol) and L-phenylalanine, tert-butyl esterhydrochloride 173 mg (0.67 mmol). Reaction was continued for 24 hours,and the crude product was eluted through a flash column (4:1hexanes:ethyl acetate), 180 mg (57%), mp 86-88° C.; ¹H NMR (CDCl₃): δ8.32 (s, 1H), 7.22 (m, 5H), 6.39 (d, 1H, J=6.6 Hz), 4.88 (q, 1H, J=6.1,J=6.8 Hz), 4.07 (s, 3H), 4.00 (s, 3H), 3.23 (d, 2H, J=5.9 Hz), 2.56 (s,3H), 1.37 (s, 9H); MS (APCI): m/z 497 (M+H).

Anal. Calcd. for C₂₅H₂₈N₄O₇: C, 60.48; H, 5.68; N, 11.28. Found: C,59.73; H, 5.53; N, 11.28.

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic aciddimethylamide (14e)

Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonylchloride (13) 250 mg (0.80 mmol) and an excess of a solution of gaseousdimethylamine bubbled into anhydrous THF. Reaction was continued for 19hours, and the crude product was eluted through a flash column (7:3hexanes:ethyl acetate), 260 mg (100%), mp 138-141° C.; ¹H NMR (CDCl₃): δ8.29 (s, 1H, 8-H), 4.03 (s, 3H, OCH₃), 3.96 (s, 3H, OCH₃), 3.28 (s, 6H,N(CH₃)₂), 2.54 (s, 3H, 6—CH₃); MS (APCI): m/z 321 (M+H).

Anal. Calcd. for C₁₄H₁₆N₄O₅: C, 52.50; H, 5.03; N, 17.49. Found: C,52.54; H, 5.01; N, 17.30.

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid methylamide(14f)

Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonylchloride (13) 250 mg (0.80 mmol) and an excess of a solution of gaseousmonomethylamine bubbled into anhydrous THF. Reaction was continued for17 hours, and the crude product was eluted through a flash column (11:9hexanes:ethyl acetate), 190 mg (76%), mp 205-206° C.; ¹H NMR (CDCl₃): δ8.32 (s, 1H), 5.83 (br s, 1H), 4.07 (s, 3H), 3.98 (s, 3H), 3.07 (d, 3H,J=5.1 Hz), 2.56 (s, 3H); MS (APCI): m/z 307 (M+1).

Anal. Calcd. for C₁₃H₁₄N₄O₅: C, 50.98; H, 4.61; N, 18.29. Found: C,51.12; H, 4.72; N, 18.25.

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid benzylamide(14g)

Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonylchloride (13) 250 mg (0.80 mmol) and benzylamine 90 μL (0.84 mmol).Reaction was continued for 24 hours, and the crude product was elutedthrough a flash column (7:3 hexanes:ethyl acetate), 260 mg (84%), mp171-173° C.; ¹H NMR (CCl₃): δ 8.32 (s, 1H), 7.32 (m, 5H), 6.12 (br s,1H), 4.68 (d, 2H, J=5.6 Hz), 4.06 (s, 3H), 3.92 (s, 3H), 2.56 (s, 3H);MS (APCI): m/z 383 (M+1).

Anal. Calcd. for C₁₉H₁₈N₄O₅: C, 59.68; H, 4.74; N, 14.65. Found: C,59.63; H, 4.94; N, 14.56.

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid,4-methoxy-benzylamide (14h)

Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonylchloride (13) 250 mg (0.80 mmol) and 4-methoxybenzylamine 0.11 mL (0.84mmol). Reaction was continued for 16 hours, and the crude product wasrecrystallized from hexanes:ethyl acetate to give yellow needles, 156 mg(47%), mp 187-189° C.; ¹H NMR (CDCl₃): δ 8.32 (s, 1H, 8-H), 7.28 (d, 2H,J=8.5 Hz), 6.85 (d, 2H, J=8.5 Hz), 6.07 (bs, 1H), 4.61 (d, 2H, J=5.6Hz), 4.05 (s, 3H), 3.97 (s, 3H), 3.76 (s, 3H), 2.56 (s, 3H); MS (APCI):m/z 413 (M+1).

Anal. Calcd. for C₂₀H₂₀N₄O₆: C, 58.25; H, 4.89; N, 13.59. Found: C,58.55; H, 4.85; N, 13.47.

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid phenylamide(14i)

Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonylchloride (13) 250 mg (0.80 mmol) and aniline 80 μL (0.84 mmol). Reactionwas continued for 40 hours, and the crude product was eluted through aflash column (3:2 hexanes:ethyl acetate), 180 mg (62%), mp 238-240° C.;¹ H NMR (CDCl₃): δ 8.34 (s, 1H), 7.81 (d, 2H, J=8.8 Hz), 7.69 (s, 1H),7.35 (t, 2H, J=7.6, 8.5 Hz), 7.11 (t, 1H, J=6.3, J=7.3 Hz), 4.17 (s,3H), 4.02 (s, 3H), 2.58 (s, 3H); MS (APCI): m/z 369 (M+H).

Anal. Calcd. for C₁₈H₁₆N₄O₅: C, 58.69; H, 4.38; N, 15.21. Found: C,58.62; H, 4.52; N, 15.06.

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid(4-methoxyphenyl)amide (14j)

Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonylchloride (13) 250 mg (0.80 mmol) and 4-anisidine 207 mg (1.68 mmol).Reaction was continued for 24 hours, and the crude product was elutedthrough a flash column (3:2 hexanes:ethyl acetate), 210 mg (66%), mp206-208° C.; ¹H NMR (CDCl₃): δ 8.33 (s, 1H), 7.71 (d, 2H, J=9.0 Hz),7.60 (s, 1H), 6.88 (d, 2H, J=8.8 Hz), 4.16 (s, 3H), 4.00 (s, 3H), 3.79(s, 3H), 2.57 (s, 3H); MS (APCI): m/z 399 (M+H).

Anal. Calcd. for C₁₉H₁₈N₄O₆: C, 57.29; H, 4.55; N, 14.06. Found: C,57.23; H, 4.73; N, 14.01.

(2,3-Dimethoxy-6-methyl-7-nitro-quinoxalin-5-yl)-piperazin-1-ylmethanone (14k)

Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonylchloride (13) 250 mg (0.80 mmol) and piperazine 138 mg (1.60 mmol).Reaction was continued for 2 hours, and the crude product was elutedthrough a flash column (8% methanol in chloroform): 250 mg (86%), mp150-152° C.; ¹H NMR (CDCl₃): δ 8.30 (s, 1H), 4.05 (s, 3H), 3.96 (s, 3H),3.81 (t, 4H, J=4.9, 5.1 Hz), 2.96 (t, 4H, J=5.1, 4.9 Hz),2.54 (s, 3H),1.84 (br s, 1H); MS (APCI): m/z 362 (M+H).

Anal. Calcd. for C₁₆H₁₉N₅O₅: C, 53.18; H, 5.30; N, 19.38. Found: C,53.08; H, 5.22; N, 18.82.

[1,4]Diazepan-1-yl-(2,3-dimethoxy-6-methyl-7-nitro-quinoxalin-5-yl)methanone(14l)

Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonylchloride (13) 250 mg (0.80 mmol) and homopiperazine 160 mg (1.60 mmol).Reaction was continued for 30 hours, and the crude product was elutedthrough a flash column (8% methanol in chloroform), 260 mg (87%), mp141-143° C.; ¹H NMR (CDCl₃): δ 8.29 (s, 1H), 4.03 (s, 3H), 3.93 (br s,7H), 3.02 (br s, 2H), 2.82 (t, 2H, J=5.4, J=5.6 Hz), 2.54 (s, 3H), 1.88(t, 2H, J=5.6, 5.4 Hz), 1.79 (bs, 1H); MS (APCI): m/z 376 (M+H).

Anal. Calcd. for C₁₇H₂₁N₅O₅: C, 54.39; H, 5.64; N, 18.66. Found: C,54.07; H, 5.57; N, 18.24.

2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid,p-tolylamide (14m)

Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonylchloride (13) 250 mg (0.80 mmol) and p-toluidine 180 mg (1.68 mmol).Reaction was carried out in refluxing tetrahydrofuran for 50 hours, andthe crude product was eluted through a flash column (7:3 hexanes:ethylacetate), 200 mg (65%), mp 214-215° C.; ¹H NMR (CDCl₃): δ 8.33 (s, 1H),7.69 (d, 2H, J=8.3 Hz), 7.65 (s, 1H), 7.15 (d, 2H, J=8.3 Hz), 4.17 (s,3H), 4.03 (s, 3H), 2.58 (s, 3H), 2.32 (s, 3H); MS (APCI): m/z 383 (M+H).

Anal. Calcd. for C₁₉H₁₈N₄O₅: C, 59.68; H, 4.74; N, 14.65. Found: C,59.97; H, 4.68; N, 14.71.

[(6-Methyl-7-Nitro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxaline-5-carbonyl)-amino]-aceticacid (15)

To a stirred mixture of[(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-amino] aceticacid tert-butyl ester (14a) 150 mg (0.37 mmol) and sodium iodide 555 mg(3.7 mmol) in 25 mL acetonitrile is added dropwise chlorotrimethylsilane0.46 mL (3.7 mmol). After addition was complete, the reaction mixturewas refluxed under an atmosphere of nitrogen for 72 hours. The reactionmixture was quenched by pouring into 100 mL water, and the aqueousmixture was concentrated to 10 mL. The residue was mixed with ethylacetate, and after stirring for 30 minutes, the product precipitated, 35mg (29%), mp 250° C. (dec.); ¹H NMR (DMSO-d₆): δ 12.55 (br s, 1H), 8.40(t, 1H, J=6.3 Hz), 7.84 (s, 1H), 4.07 (d, 2H, J=6.3 Hz), 2.43 (s, 3H);MS (APCI): m/z 323 (M+H).

Anal. Calcd. for C₁₂H₁₀N₄O₇: C, 44.73; H, 3.13; N, 17.39. Found: C,41.38; H, 3.12; N, 15.79.

Example 2

Scheme II procedure follows as indicated below.

6-Methyl-1-7-nitro-quinoxaline-2,3-dione-5-hydrazide (4)

From Quinoxaline-2,3-dione-5-methyl ester (A) (Compound 8 of Scheme I)

A solution of A (1.00 g, 3.6 mmol) in anhydrous hydrazine (10 mL) wasstirred at room temperature under nitrogen for 24 hours. The solvent wasremoved under reduced pressure, and the residue was taken up in boilingwater and filtered hot. Upon cooling the hydrazide precipitated as ayellow, crystalline solid (806 mg, 80%).

MS (Cl) m/z=280 (M+1).

5-(5-Amino-[1,3,4]oxadiazol-2-yl)-6-methyl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione(6)

A mixture of compound 4 (300 mg, 1.08 mmol) and KHCO₃ (124 mg, 1.24mmol) in water (20 mL) was heated to 70° C., at which point all solidwent into solution. A solution of cyanogen bromide (126 mg, 1.19 mmol)in water (3 mL) was added dropwise. Approximately 30 seconds afteraddition was complete, the product began to precipitate. The reactionmixture was kept at 70° C. for 1 hour and upon cooling, compound 6 wascollected and washed with both water and acetone (84 mg, 26%).

MS (Cl) m/z=305 (M+1).

6-Methyl-7-nitro-5-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-1,4-dihydro-quinoxaline-2,3-dione(5)

A suspension of compound 4 (150 mg, 0.54 mmol) in anhydrous THF (10 mL)under nitrogen was treated dropwise with a 20% phosgene solution intoluene (10 mL). After stirring for 23 hours at room temperature, theprecipitate was collected and washed with methanol to give an off-whitesolid (82 mg, 50%).

MS (Cl) m/z=306 (M+1).

The compounds of the invention exhibit valuable biological propertiesbecause of their strong excitatory amino acid (EAA) antagonizingproperties at one of several binding sites on glutamate receptors: theAMPA ((RS)-amino-3-hydroxy-5-methyl-4-isoxazole)-propionic acid (orkainic acid) binding site on AMPA (non-NMDA) receptors or the glycinesite of NMDA receptors.

The compounds of the present invention exhibit binding affinity for theAMPA receptors measured as described in Honore T., et al., NeuroscienceLetters, 1985;54:27-32. Preferred compounds demonstrate IC₅₀ values:<100 μM in this assay. The compounds of the present invention exhibitbinding affinity for the kainate site (non-NMDA receptor) measured asdescribed in London E. D. and Coyle J., Mol. Pharmacol., 1979;15:492.The compounds of the present invention exhibit binding affinity for theglycine site of the NMDA receptor measured as described in Jones S. M.,et al., Pharmacol. Methods, 1989;21:161. To measure functional AMPAantagonist activity, the effects of the agent on AMPA-induced neuronaldamage in primary cortical neuronal cultures was examined usingtechniques similar to those outlined by Koh J-Y., et al., J. Neurosci.,1990;10:693. In addition, the neuronal damage produced by long-termexposure to 100 μM AMPA may be measured by the release of the cytosolicenzyme lactate dehydrogenase (LDH).

Selected compounds of the present invention were tested by one or moreof the above-described assays. The data obtained in the assays is setforth in Table 1 below. The IC₅₀ values set forth in Table 1 is ameasure of the concentration (EM) of the test substance which inhibits50% of an induced release from the tested receptors.

TABLE OF BIOLOGICAL ACTIVITY 1.5-(5-Amino-[1,3,4]oxadiazo-1-2yl)-6-methyl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione

2. 6-Methyl-7-nitro-5-(-oxo-4,5-diyhdro-[1,3,4]oxadiazo-1-2-yl-1,4-dihydro-quinoxaline-2,3-dione

Example IC₅₀ AMPA IC₅₀ GLY 1 0.4 0.06 2 0.5 —

While the forms of the invention herein disclosed constitute presentlypreferred embodiments, many others are possible. It is not intendedherein to mention all of the possible equivalent forms or ramificationsof the invention. It is understood that the terms used herein are merelydescriptive rather than limiting, and that various changes may be madewithout departing from the spirit or scope of the invention.

What is claimed is:
 1. A compound of formula I:

wherein R is a nitrogen heterocyclic ring selected from any one of thefollowing rings

 optionally substituted by one or more substituents selected from: alkylof from 1 to 4 carbon atoms, hydroxyl, alkoxy of from 1 to 4 carbonatoms, —CF₃, —CN, —amino, —C(O)R₁₁, or —(CH₂)_(n)-aryl of from 6 to 12carbon atoms; or R is

 and wherein R₁ is H or alkyl of from 1 to 4 carbon atoms; R₂ ishydrogen; R₃ is hydrogen; R₄ is each independently H, alkyl of from 1 to4 carbon atoms, cycloalkyl of from 5 to 7 carbon atoms, alkenyl of from2 to 6 carbon atoms, halogen, haloalkyl of from 1 to 6 carbon atoms,nitro, cyano, SO₂CF₃, CH₂SO₂R₇,(CH₂)_(m)CO₂R₇, (CH₂₎ _(m)CONR₇R₈,(CH₂)_(m)SO₂NR₈R₉, or NHCOR₇; R₅ is H or alkyl of from 1 to 4 carbonatoms; R₇, R₈, R₉, and R₁₀are each independently selected from hydrogen,alkyl of from 1 to 4 carbon atoms, cycloalkyl of from 5 to 7 carbonatoms, haloalkyl of from 1 to 4 carbon atoms, or —(CH₂)_(m)R₁₁; R₁₁ isalkyl or alkoxy of from 1 to 4 carbon atoms, hydroxy, or amino; m is aninteger of from 0 to 4; n is an integer of from 0 to 4; R′ and R″ areindependently H, alkyl of from 1-4 carbon atoms, cycloalkyl of from 5 to6 carbon atoms, or heterocycloalkyl of from 5-7 members with up to 4heteroatoms selected from the group consisting of nitrogen, oxygen andsulfur; or a pharmaceutically acceptable salt thereof.
 2. A compoundselected from the group consisting of named:[(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-amino] aceticacid tert-butyl ester;[(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-methylamino]-aceticacid, tert-butyl ester;3-[(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-amino]-propionicacid, tert-butyl ester;(S)-2-[(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-amino]-3-phenylpropionicacid, tert-butyl ester;2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic aciddimethylamide; 2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylicacid methylamide;2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acidbenzylamide; 2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylicacid, 4-methoxy-benzylamide;2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acidphenylamide; 2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylicacid (4-methoxyphenyl)amide;(2,3-Dimethoxy-6-methyl-7-nitro-quinoxalin-5-yl)-piperazin-1-ylmethanone;[1,4]Diazepan-1-yl-(2,3-dimethoxy-6-methyl-7-nitro-quinoxalin-5-yl)methanone;and 2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid,p-tolylamide.